Brian O. Patrick

Acyclic Chelate with Ideal Properties for 68Ga PET Imaging Agent Elaboration

We have investigated novel bifunctional chelate alternatives to the aminocarboxylate macrocycles NOTA (N(3)O(3)) or DOTA (N(4)O(4)) for application of radioisotopes of Ga to diagnostic nuclear medicine and have found that the linear N(4)O(2) chelate H(2)dedpa coordinates (67)Ga quantitatively to form [(67)Ga(dedpa)](+) after 10 min at RT. Concentration-dependent coordination to H(2)dedpa of either (68)Ga or (67)Ga showed quantitative conversion to the desired products with ligand concentrations as low as 10(-7) M. With (68)Ga, specific activities as high as 9.8 mCi nmol(-1) were obtained without purification. In a 2 h competition experiment against human apo-transferrin, [(67)Ga(dedpa)](+) showed no decomposition. Two bifunctional versions of H(2)dedpa are also described, and these both coordinate to (67)Ga at RT within 10 min. Complete syntheses, characterizations, labeling studies, and biodistribution profiles of the (67)Ga complexes are presented for the new platform chelates. The stability of these platform chelates is higher than that of DOTA.

Amidate complexes of titanium and zirconium: a new class of tunable precatalysts for the hydroamination of alkynesElectronic supplementary information (ESI) available: experimental details. See http://www.rsc.org/suppdata/cc/b3/b304176j/

A series of bis(amidate)group 4-bis(amido) complexes have been prepared, characterized and have been shown to be highly tunable precatalysts for both the intra- and intermolecular hydroamination of alkynes.

Sintokamides A to E, Chlorinated Peptides from the Sponge Dysidea sp. that Inhibit Transactivation of the N-Terminus of the Androgen Receptor in Prostate Cancer Cells

The new chlorinated peptides sintokamides A to E (1-5) have been isolated from specimens of the marine sponge Dysidea sp. collected in Indonesia. Their structures were elucidated by a combination of spectroscopic and single-crystal X-ray diffraction analyses. Sintokamide A (1) is an inhibitor of N-terminus transactivation of the androgen receptor in prostate cancer cells.

Synthesis of 1,1-disubstituted alkyl vinyl sulfides via rhodium-catalyzed alkyne hydrothiolation: scope and limitations.

Described herein are the scope and limitations using Tp*Rh(PPh(3))(2) as a catalyst for alkyne hydrothiolation with alkyl thiols. In general, catalytic hydrothiolation proceeds in high yields and with high regioselectivity for a wide range of alkynes and thiols. A variety of functional groups were well-tolerated, including nitriles, amines, halogens, ethers, esters and silanes, although strongly coordinating groups were found to be incompatible with hydrothiolation. Both sterically encumbered alkynes and thiols were successful in hydrothiolation. Electron rich alkynes react more rapidly than electron deficient alkynes. Overall, this hydrothiolation protocol provides convenient access to a variety of functionalized branched alkyl vinyl sulfides.

Synthesis, structure and magnetic properties of 3D interpenetrating nets of M(pyrazine)[Au(CN)2]2 (M=Cu, Ni, Co) supported by aurophilic interactions

Abstract New inorganic coordination polymers of the form M(pyrazine)[Au(CN)2]2 (M=Cu (1); Ni (2); Co (3)) have been prepared and the copper(II) analogue structurally characterised. The X-ray analysis revealed two 3D interpenetrating α-polonium networks consisting of 1D chains of Cu–pyrazine units connected by [Au(CN)2] bridges. The two networks are connected via weak aurophilic interactions (AuAu: 3.4729(2) A). Thermogravimetric analysis of all three compounds indicated the robust nature of these 3D systems, with decomposition beginning at 260 (1), 406 (2) and 360°C (3). The magnetic susceptibility of 1 shows a maximum in χM at 5.0 K; these data could be fitted to the theoretical expressions for either a 1D or a 2D Heisenberg antiferromagnetic array (J=−2.74 cm−1, g=2.32 and J=−3.45 cm−1, g=2.33, respectively). The magnetic susceptibility versus temperature data for 2 and 3 showed effects primarily associated with single-ion zero-field splitting; any weak antiferromagnetic coupling in these systems is very weak and hence was not quantified. Although the aurophilic interactions between the [Au(CN)2] units may positively influence both the formation of an interpenetrating structure and its subsequent thermal stability, the incorporation of anionic [Au(CN)2] units into M(pyrazine) systems does not seem to significantly increase magnetic interactions.

Cladoniamides A−G, Tryptophan-Derived Alkaloids Produced in Culture by Streptomyces uncialis

Cladoniamides A-G (3- 9) have been isolated from cultures of Streptomyces uncialis, and their structures have been elucidated by a combination of spectroscopic analysis and an X-ray diffraction analysis of cladoniamide A (3). The cladoniamides have unprecedented rearranged and degraded alkaloid skeletons with putative biogenetic origins from indolocarbazole precursors. Cladoniamide G (9) is cytotoxic to MCF-7 cells in vitro at 10 microg/mL.

N-Aryl-substituted 3-(β-D-glucopyranosyloxy)-2-methyl-4(1H)-pyridinones as agents for Alzheimer's therapy

Molecules designed to sequester, redistribute and/or remove metal ions are attractive therapeutic agents in neurodegenerative diseases such as Alzheimers disease. The multifactorial nature of the condition and the generally poor target specificity associated with metal ion-binding therapy has led to the development of multifunctional 3-hydroxy-4-(1H)-pyridinone pro-ligands. The excellent qualities of the basic 3-hydroxy-4-pyridinone framework as a low toxicity metal chelator and an antioxidant, as well as its antibacterial and analgesic properties among other functions, inspired us to functionalize it with a framework derived from thioflavin-T, the well-known traditional dye used as a marker to detect amyloid deposits in tissue sections. Thus 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone (HL1), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (HL2), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL3), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL4), 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (HL5) and 2-methyl-3-hydroxy-1-[4-(4-bromophenyl)-2-thiazolyl]-4(1H)-pyridinone (HL6) were obtained. Glycosylation, as well as incorporation of structures mimicking those of known amyloid imaging agents, may target drug action to the site of interest, the metal-overloaded amyloid plaques in the Alzheimers brain. The pro-ligands were assessed for their antioxidant activity, cytotoxicity and ability to interfere with metal ion-induced amyloid peptide aggregation to screen promising lead compounds. Finally, in a brain uptake study with a radiolabeled glucoconjugate pyridinone, 3-(β-D-glucopyranosyloxy)-1-[4-(4-[125I]iodophenyl)-2-thiazolyl]-2-methyl-4(1H)-pyridinone ([125I]-GL7) was shown to cross the blood–brain barrier using an in situ rat brain perfusion technique.

The synthesis, structural characterization, and in vitro anti-cancer activity of chloro(p-cymene) complexes of ruthenium(II) containing a disulfoxide ligand

Abstract Two diruthenium(II) complexes [RuCl2(p-cymene)]2(μ-BESE) (1), [RuCl2(p-cymene)]2(μ-BESP) (2), and the mononuclear salt [RuCl(p-cymene)(BESE)]PF6 (3), containing the disulfoxides BESE and BESP, were synthesized and characterized by elemental analysis, and NMR and IR spectroscopies, and were shown to contain S-bound sulfoxide groups; the disulfoxides are EtS(O)(CH2)nS(O)Et, where n=2 (BESE) or 3 (BESP). Complexes 1 and 3 were also characterized by X-ray crystallography. Preliminary in vitro tests of 1 and 3 were conducted using the MTT assay, which measures mitochondrial dehydrogenase activity as an indication of cell viability; these complexes showed in vitro anti-cancer activity against a human mammary cancer cell line (MDA-MB-435s) with IC50 values of 360 and 55 μM, respectively.

Formazans as β-diketiminate analogues. Structural characterization of boratatetrazines and their reduction to borataverdazyl radical anions

Formazans react with boron triacetate to produce boratatetrazines, which can be reduced to yield borataverdazyl radical anions--the first boron containing verdazyl radicals.

Redox-active, near-infrared dyes based on ‘Nindigo’ (indigo-N,N′-diarylimine) boron chelate complexes

Reactions of indigo-N,N′-diarylimine (‘Nindigo’) derivatives with BF3·Et2O give mono- or bis-BF2 chelate complexes 2 or 3 respectively. The product distribution between 2 and 3 is sensitive to the auxiliary base and solvent. Although the bis-BF2 complexes 3 are isolable, they gradually decompose in solution to the corresponding mono-BF2 species 2; this process is accelerated by water. The instability of 3 is believed to be due to ring stain effects based on structural analyses of 2. Electrochemical studies of 2 reveal one quasi-reversible oxidation process and two irreversible reductions, whereas derivatives of 3 possess a reversible oxidation and two sequential reversible reductions. The electronic spectra of 2 and 3 contain intense (e ∼ 3 × 104 M−1 cm−1) long-wavelength absorptions near 650 nm and 750 nm respectively. Both series of compounds are weakly emissive in the near-infrared. Time-dependent DFT calculations reveal the electronic transitions to be π–π* in nature.